15 million Americans, including 6 million children, have a potentially life-threatening food allergy. There is no cure, and effective prevention and treatment strategies are lacking. Moreover, little is known regarding the factors that account for the rise in prevalence and severity of this disease in recent years. Oral tolerance to food proteins is thought to develop in the small intestine. Here, food antigens are taken up and transferred to CD103+ dendritic cells (DCs) that then migrate to the mesenteric lymph nodes where they induce the generation of antigen-specific T regulatory cells (Tregs). Tregs are characterized by expression of the transcription factor, Foxp3, and play a key role in suppressing immune responses both to self-antigens (thymic Tregs) as well as innocuous antigens (peripherally-induced Tregs) found in commensal flora and food proteins. In mice, Tregs are critical for the establishment of oral tolerance, and adoptive transfer of antigen-specific Tregs can also protect against food-induced anaphylaxis after establishment of allergic sensitization. Mice that lack peripherally-induced Tregs spontaneously develop Th2 inflammation in the GI tract and antibodies to components of mouse chow. Both mice and humans with mutations in FOXP3 are more likely to develop allergic disease. The frequency of milk-specific Tregs was higher in children able to tolerate heated milk compared to those allergic to all forms of milk or nonatopic controls, suggesting at least a transient role for Tregs in development of acquired tolerance in humans. This notion was supported by a recent study demonstrating that, after oral immunotherapy, children with peanut allergy who maintained clinical desensitization to peanut exhibited persistent hypomethylation of the FOXP3 locus, while those who only displayed temporary loss of clinical reactivity also only temporarily exhibited demethylation of FOXP3. We have shown that total Treg numbers are paradoxically increased in patients with food allergy. However, Tregs from allergic subjects were found to produce Th2 cytokines, suggesting they may promote rather than inhibit allergic inflammation. Our current efforts are directed at investigating how Tregs may contribute to the development versus protection against food allergic reactions.